This proposal presents a step-wise multi-center approach to provide meaningful new improvements in immunosuppression for pediatric kidney transplantation, using the first successful single center experience with complete steroid avoidance as a foundation proceeding to a modification to reduce calcineurin-inhibitor nephrotoxicity and chronic allograft nephropathy (CAN), and finally, the introduction of a tolerance induction protocol that could eliminate all maintenance immunosuppressive medication post-transplantation. Patient recruitment will be carried out at 30 centers through NAPRTCS. Project I will be a controlled, open-label, randomized (1:1), multi-center clinical trial in 300 patients aged 0-20 years that will compare two steroid-free immunosuppressive regimens, both with similar extended daclizumab induction to replace steroids: (1) the established single center protocol with standard dose tacrolimus and mycophenalate mofetit (MMF) and (2) the other, a new protocol with half-dose tacrolimus and substitution of sirolimus for MMF. The primary end point will be an improvement in graft function at 1 and 2 years, while maintaining equivalency for acute and sub-acute rejection. Project II will be a pilot study to establish renal allograft tolerance in ten pediatric kidney recipients aged 13-18 years, through a non-myeloablative conditioning regimen that includes cyclophosphamide, a humanized anti-CD2 monoclonal, antibody, thymic irradiation, followed by cyclosporine as the only post-transplant immunosuppressive agent. Cyclosporine will be withdrawn after 60 days in recipients with detectable multi-lineage white blood cell chimerism. The primary endpoint will be 24-month graft survival without maintenance immunosuppression. Protocol allograft biopsies and mechanistic studies will be linked to both projects to further elucidate the molecular mechanisms of graft rejection, drug nephrotoxicity, CAN and tolerance. These will include microarray analysis for global expression profiling of the allograft and periphery, quantitative RT-PCR for cytokine monitoring, sirius red staining for quantitation of allograft fibrosis, as well as chimerism and tolerance assays. The success of these protocols should result in elimination of steroid toxicity, normalization of growth, extended long-term graft survival with excellent function, and the potential applicability of these protocols to adults and other solid organ transplant recipients with significant economic benefit. [unreadable] [unreadable]